A multicenter, randomized, placebo-controlled, double-blind phase II trial evaluating the optimal dose, efficacy and safety of LC 15-0444 in patients with type 2 diabetes.

AIM: The objective of this study was to evaluate the optimal dose, efficacy and safety of a novel dipeptidyl peptidase-4 (DPP-IV) inhibitor, LC15-0444, in Korean subjects with type 2 diabetes mellitus treated by diet and exercise. METHODS: This study was a double-blind, randomized, multicenter and parallel-group, dose-range finding study. We enrolled 145 patients (91 men and 54 women) with a median age of 53 years and a median body mass index of 25.1 kg/m(2) . The median baseline fasting plasma glucose (FPG) was 8.1 mmol/l, the median HbA1c was 7.9% and the median time since the diagnosis of diabetes was 3 years. After 2 weeks of an exercise/diet programme followed by 2 weeks of a placebo period, the subjects were randomized to one of the four following groups for a 12-week active treatment period: placebo and 50, 100 or 200 mg of LC15-0444. RESULTS: All three doses of LC15-0444 significantly reduced the HbA1c from baseline compared to the placebo group (-0.06 vs. -0.98, -0.74 and -0.78% in the placebo and 50, 100 and 200 mg groups, respectively), without a significant difference between the doses. Subjects with a higher baseline HbA1c (≥8.5%) had a greater reduction in HbA1c. Insulin secretory function, as assessed using homeostasis model assessment-beta cell, C-peptide and the insulinogenic index, improved significantly with LC15-0444 treatment. Insulin sensitivity, as assessed using homeostasis model assessment-insulin resistance, also improved significantly after 12 weeks of treatment. The 50 and 200 mg groups had significantly reduced total cholesterol and low-density lipoprotein cholesterol levels at 12 weeks compared to the placebo group. No dosage of LC15-0444 affected weight or waist circumference. The incidences of adverse events were similar in all study subjects. CONCLUSIONS: LC15-0444 monotherapy (50 mg for 12 weeks) improved the HbA1c, FPG level, oral glucose tolerance test results, ß-cell function and insulin sensitivity measures, and was well tolerated in Korean subjects with type 2 diabetes.

Cellular and molecular mechanism for Kilham rat virus-induced autoimmune diabetes in DR-BB rats.

Kilham rat virus (KRV) causes autoimmune diabetes in diabetes-resistant BioBreeding (DR-BB) rats; however, the mechanism by which KRV induces autoimmune diabetes without the direct infection of beta cells is not well understood. We first asked whether molecular mimicry, such as a common epitope between a KRV-specific peptide and a beta cell autoantigen, is involved in the initiation of KRV-induced autoimmune diabetes in DR-BB rats. We found that KRV peptide-specific T cells generated in DR-BB rats infected with recombinant vaccinia virus expressing KRV-specific structural and nonstructural proteins could not induce diabetes, indicating that molecular mimicry is not the mechanism by which KRV induces autoimmune diabetes. Alternatively, we asked whether KRV infection of DR-BB rats could disrupt the finely tuned immune balance and activate autoreactive T cells that are cytotoxic to beta cells, resulting in T cell-mediated autoimmune diabetes. We found that both Th1-like CD45RC+CD4+ and cytotoxic CD8+ T cells were up-regulated, whereas Th2-like CD45RC-CD4+ T cells were down-regulated, and that isolated and activated CD45RC+CD4+ and CD8+ T cells from KRV-infected DR-BB rats induced autoimmune diabetes in young diabetes-prone BioBreeding (DP-BB) rats. We conclude that KRV-induced autoimmune diabetes in DR-BB rats is not due to molecular mimicry, but is due to a breakdown of the finely tuned immune balance of Th1-like CD45RC+CD4+ and Th2-like CD45RC-CD4+ T cells, resulting in the selective activation of beta cell-cytotoxic effector T cells.

Impaired homeostatic mechanism of potassium handling after acute oral potassium load in diabetes mellitus.

Chronic stable diabetic patients (n = 6) were compared with healthy control subjects (n = 5) after acute oral intake of 50 mEq of potassium chloride (KCl) to investigate for possible derangements of homeostatic responses for acute term (3 hrs) to acute potassium load. Plasma renin activity (PRA), plasma aldosterone (PA), and transtubular potassium concentration gradient (TTKG) known as a useful semiquantative index of distal nephron potassium secretion were measured. All the baseline parameters were comparable between diabetic and non-diabetic subjects except for significantly reduced creatinine clearance in diabetics (mean +/- SEM, 105 +/- 4 vs. 85 +/- 5 ml/min, p < 0.05). Following acute oral KCl load, the peak increases of serum potassium changes from basal levels were noted at 2 hours in both groups, but were higher in diabetic subjects (mean +/- SEM, 0.42 +/- 0.06 vs. 0.62 +/- 0.09 mEq/L). Also, 4 out of 6 diabetic subjects but none of the control subjects at 2 hours after oral KCl load became hyperkalemic ( > 5.0 mEq/L). PRA did not show any significant changes, whereas PA was increased simultaneously with increments in serum potassium in both groups, with blunted increases in the diabetics. However, TTKG was increased prominently in control subjects (8.18 from 4.98), but only slightly in diabetic subjects (4.55 from 4.18), with statistical difference between the two groups (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Heterogeneous changes of serum potassium levels in NIDDM patients on oral glucose load.

Ten noninsulin dependent diabetic patients (NIDDM) without baseline hyperkalemia and with normal aldosterone levels when given 100 g of glucose orally revealed heterogeneous responses in serum potassium changes. Six diabetics had paradoxical increases in serum potassium levels averaged 0.44 mEq/L (range, 0.1 to 1.1 mEq/L) and were accompanied by increases in plasma aldosterone levels. On the contrary, four other noninsulin dependent diabetics and four nondiabetic control subjects had gradual decreases in serum potassium levels with simultaneous decreases in plasma aldosterone levels. These rises and falls in serum potassium concentrations coincided with changes in serum osmolality related mostly to the degree of increases in serum glucose following oral glucose administration. pH of venous blood didn't show any relevant and significant changes with changes of serum potassium levels following oral glucose load. This finding suggests that osmotic mechanisms with various degree of well known abnormal insulin secretion and resistance to insulin action in target tissues in NIDDM patients may account for these heterogeneous responses in serum potassium changes after glucose load, and normal aldosterone levels may not be sufficient to prevent glucose induced increases in serum potassium in NIDDM patients.